Special Issue Information

Dear Colleagues,

Analogues of natural nucleosides have long played pivotal roles in the treatment of viral infections and cancer. A vast majority of FDA approved drugs to treat viral infections are nucleoside analogues, including but not limited to AZT, ddI, ddC, FTC, 3TC (HIV), entecavir, lamivudine, telbuvidine (HBV), and acyclovir (HSV). In addition, a number of drugs currently under clinical development for treating HCV infection, which fall under the category of polymerase inhibitors, are nucleoside analogues. With regard to chemotherapy, nucleoside or nucleobase analogues were among the first to be introduced for the treatment of cancer. Some examples of FDA-approved anticancer nucleosides/nucleobases include Ara-C (AML/leukemia), 5-FU (skin cancer), and gemcitabine (breast, pancreatic, lung, and ovarian cancers). A number of these nucleoside analogues act as antimetabolites, compete with natural nucleosides, and interact with a large number of intracellular targets to induce cytotoxicity. A lot of work is currently underway in identification and characterization of nucleoside transporters and the enzymes of nucleoside metabolism. Many of these enzyme inhibitors are derived from nucleoside framework, and are targeted to reverse transcriptases and other polymerases, deaminases, kinases, and hydrolases, and have found additional uses in a wide variety of bacterial infections such as malaria and tuberculosis. A number of nucleoside analogues get incorporated during replication or DNA excision repair synthesis, leading to chain termination. Recent research on DNAzymes, which cleave at predetermined sequences within RNA, suggests that incorporation of locked nucleoside analogues into DNAzymes improves their ability to gain access and cleave at highly-structured RNA targets. Furthermore, biophysical investigations of certain locked nucleoside analogues have revealed that they possess hybridization and mismatch discrimination attributes similar to those of locked nucleic acid (LNA) but with greatly improved resistance to exonuclease digestion. Considerable advances have also been made in the area of adenosine receptor agonists/antagonists, which play significant roles in regulation of myocardial oxygen consumption, coronary blood flow, antiinflammatory effects, release of neurotransmitters, and control of immune responses. A vast majority of these agonists/antagonists are derived from adenosine or xanthine family. Finally, a lot of research of mainly academic interest is being carried out on nucleoside analogues as potentially new genetic alphabets. With non-standard hydrogen-bonding topologies, shape complementarity, and/or hydrophobic interfaces, these unnatural bases could pair with complementary natural or unnatural bases to confer enough selectivity and efficiency during transcription, translation, and replication, thus expanding the genetic information. Articles falling in any of these described or related areas are welcome for inclusion of this special issue of Molecules on Nucleoside Analogues, to be published by MDPI, Switzerland.

Abstract: The genome is constantly exposed to mutations that can originate during replication or as a result of the action of both endogenous and/or exogenous damaging agents [such as reactive oxygen species (ROS), UV light, genotoxic environmental compounds, etc.]. Cells have developed a set of specialized mechanisms to counteract this mutational burden. Many cancer cells have defects in one or more DNA repair pathways, hence they rely on a narrower set of specialized DNA repair mechanisms than normal cells. Inhibiting one of these pathways in the context of an already DNA repair-deficient genetic background, will be more toxic to cancer cells than to normal cells, a concept recently exploited in cancer chemotherapy by the synthetic lethality approach. Essential to all DNA repair pathways are the DNA pols. Thus, these enzymes are being regarded as attractive targets for the development of specific inhibitors of DNA repair in cancer cells. In this review we examine the current state-of-the-art in the development of nucleotide analogs as inhibitors of repair DNA polymerases.

Abstract: Replicating cells undergo DNA synthesis in the highly regulated, S-phase of the cell cycle. Analogues of the pyrimidine deoxynucleoside thymidine may be inserted into replicating DNA, effectively tagging dividing cells allowing their characterisation. Tritiated thymidine, targeted using autoradiography was technically demanding and superseded by 5-bromo-2-deoxyuridine (BrdU) and related halogenated analogues, detected using antibodies. Their detection required the denaturation of DNA, often constraining the outcome of investigations. Despite these limitations BrdU alone has been used to target newly synthesised DNA in over 20,000 reviewed biomedical studies. A recent breakthrough in “tagging DNA synthesis” is the thymidine analogue 5-ethynyl-2′-deoxyuridine (EdU). The alkyne group in EdU is readily detected using a fluorescent azide probe and copper catalysis using ‘Huisgen’s reaction’ (1,3-dipolar cycloaddition or ‘click chemistry’). This rapid, two-step biolabelling approach allows the tagging and imaging of DNA within cells whilst preserving the structural and molecular integrity of the cells. The bio-orthogonal detection of EdU allows its application in more experimental assays than previously possible with other “unnatural bases”. These include physiological, anatomical and molecular biological experimentation in multiple fields including, stem cell research, cancer biology, and parasitology. The full potential of EdU and related molecules in biomedical research remains to be explored.

Abstract: 5-Substituted-4-thio-2’-deoxyuridine nucleosides have been chemically synthesized and studied by NMR and UV spectroscopy. The results have been analyzed and discussed in connection with the previous data. The imino proton signal and the carbon signal of the thiocarbonyl group in the 5-substituted-4-thio-2’-deoxyuridines were found to be at much lower field, offering a potential for monitoring these modified bases at the DNA level. All 4-thionucleosides have strong absorptions at around 340 nm and consequently would be useful as potential UVA-induced anticancer agents.

Abstract: There are more than 100 different ribonucleoside structures incorporated as post-transcriptional modifications, mainly in tRNA and rRNA of both prokaryotes and eukaryotes, and emerging evidence suggests that these modifications function as a system in the translational control of cellular responses. However, our understanding of this system is hampered by the paucity of information about the complete set of RNA modifications present in individual organisms. To this end, we have employed a chromatography-coupled mass spectrometric approach to define the spectrum of modified ribonucleosides in microbial species, starting with Mycobacterium bovis BCG. This approach revealed a variety of ribonucleoside candidates in tRNA from BCG, of which 12 were definitively identified based on comparisons to synthetic standards and 5 were tentatively identified by exact mass comparisons to RNA modification databases. Among the ribonucleosides observed in BCG tRNA was one not previously described in tRNA, which we have now characterized as N6,N6-dimethyladenosine.

Abstract: We describe the synthesis of terpyridine modified DNA strands which selectively form DNA nanotubes through orthogonal hydrogen bonding and metal complexation interactions. The short DNA strands are designed to self-assemble into long duplexes through a sticky-end approach. Addition of weakly binding metals such as Zn(II) and Ni(II) induces the formation of tubular arrays consisting of DNA bundles which are 50-200 nm wide and 2-50 nm high. TEM shows additional long distance ordering of the terpy-DNA complexes into fibers.

Abstract: Nucleic acids are able to adopt a plethora of structures, many of which are of interest in therapeutics, bio- or nanotechnology. However, structural and biochemical stability is a major concern which has been addressed by incorporating a range of modifications and nucleoside derivatives. This review summarizes the use of locked nucleic acid (LNA) and un-locked nucleic acid (UNA) monomers in functional nucleic acids such as aptamers, ribozymes, and DNAzymes.

Abstract: The review summarizes data evaluating the role of adenosine receptor signaling in murine hematopoietic functions. The studies carried out utilized either non-selective activation of adenosine receptors induced by elevation of extracellular adenosine or by administration of synthetic adenosine analogs having various proportions of selectivity for a particular receptor. Numerous studies have described stimulatory effects of non-selective activation of adenosine receptors, manifested as enhancement of proliferation of cells at various levels of the hematopoietic hierarchy. Subsequent experimental approaches, considering the hematopoiesis-modulating action of adenosine receptor agonists with a high level of selectivity to individual adenosine receptor subtypes, have revealed differential effects of various adenosine analogs. Whereas selective activation of A1 receptors has resulted in suppression of proliferation of hematopoietic progenitor and precursor cells, that of A3 receptors has led to stimulated cell proliferation in these cell compartments. Thus, A1 and A3 receptors have been found to play a homeostatic role in suppressed and regenerating hematopoiesis. Selective activation of adenosine A3 receptors has been found to act curatively under conditions of drug- and radiation-induced myelosuppression. The findings in these and further research areas will be summarized and mechanisms of hematopoiesis-modulating action of adenosine receptor agonists will be discussed.